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PubMed2006

The TCR Vbeta signature of bacterial superantigens spreads with stimulus strength.

Superantigens (Sags) induce large-scale stimulation of T lymphocytes by a mechanism distinct from conventional antigen presentation, involving direct MHC binding and stimulation of TCR families based on Vbeta gene usage. The specific Vbeta targets of a given Sag have, since the earliest studies in murine models, been considered a hallmark of that toxin. Bacterial Sags are implicated in the aetiology of a wide range of human diseases, although their role has been most clearly defined in toxic shock syndrome. While Sags have been defined by the Vbeta-specific changes in T cell repertoire they induce, human studies of in vitro stimulation or analysis of cells from infected patients have produced inconsistent findings. Here we have evaluated the contribution of HLA allelic polymorphisms and strength of stimulus to this response. We show that there are differences in binding and presentation of the staphylococcal Sag, staphylococcal enterotoxin A (SEA), by different HLA-DR alleles. We also show that the TCR Vbeta response, previously thought to be a fixed property defining a given Sag, varies with stimulus strength such that a broader repertoire of response is seen at higher concentrations or following presentation by high-binding class II types. Responses of human Vbeta8 and Vbeta1 to SEA, Vbeta5 to SEB and of Vbeta12 and Vbeta13 to streptococcal pyrogenic exotoxin A are absolutely dependent on stimulus strength. These findings have important implications for heterogeneity in the response to Sags and the consequent differences in susceptibility to severe toxic shock.

Antigen Presentation↗

PubMed2005

Interaction between KIR3DL1 and HLA-B*57 supertype alleles influences the progression of HIV-1 infection in a Zambian population.

KIR and HLA loci are both highly polymorphic, and some HLA class 1 products bind and trigger cell-surface receptors specified by KIR genes. We examined whether KIR genes act in concert with HLA-B locus to control HIV-1 infection in a sample of Zambian patients. DNA samples from 88 Zambian patients with HIV-1 were examined. Patients were classified as either slow progressors (SP; n = 54) or rapid progressors (RP; n = 34) to AIDS. All were typed for HLA-B and KIR genes. Our results reveal an association between B*57 supertype (B*57s, which includes B*57 and B*58 alleles) and delayed progression to AIDS (p = 0.0007 by pc = 0.015; OR = 5.25). We also observed an increase incidence of Bw4-I80 in patients with slow progression (p = 0.001 by pc = 0.003, OR = 5). This increase was found to be secondary to B*57s. The presence of both KIR3DL1 and B*57S has a significant effect on progression to AIDS (p = 0.0008; OR = 5.61). B*57s genotypes with another HLA-B allele different from those in the trans position, which also had a specificity different to Bw4-I80 (Bw4-T80 or Bw6), was also greater in the SP than in the RP group (p = 0.00003; OR = 10.11). The presence of the inhibitory allele KIR3DL1 in combination with the HLA-B*57s alleles that contain the Bw4-I80 epitope, has a highly protective effect against progression to AIDS in Zambian patients.

Acquired Immunodeficiency Syndrome↗

PubMed2002

Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS.

Natural killer (NK) cells provide defense in the early stages of the innate immune response against viral infections by producing cytokines and causing cytotoxicity. The killer immunoglobulin-like receptors (KIRs) on NK cells regulate the inhibition and activation of NK-cell responses through recognition of human leukocyte antigen (HLA) class I molecules on target cells KIR and HLA loci are both highly polymorphic, and some HLA class I products bind and trigger cell-surface receptors specified by KIR genes. Here we report that the activating KIR allele KIR3DS1, in combination with HLA-B alleles that encode molecules with isoleucine at position 80 (HLA-B Bw4-80Ile), is associated with delayed progression to AIDS in individuals infected with human immunodeficiency virus type 1 (HIV-1). In the absence of KIR3DS1, the HLA-B Bw4-80Ile allele was not associated with any of the AIDS outcomes measured. By contrast, in the absence of HLA-B Bw4-80Ile alleles, KIR3DS1 was significantly associated with more rapid progression to AIDS. These observations are strongly suggestive of a model involving an epistatic interaction between the two loci. The strongest synergistic effect of these loci was on progression to depletion of CD4(+) T cells, which suggests that a protective response of NK cells involving KIR3DS1 and its HLA class I ligands begins soon after HIV-1 infection.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Contribution of KIR3DL1/3DS1 to ankylosing spondylitis in human leukocyte antigen-B27 Caucasian populations.

Killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) loci are both highly polymorphic, and some HLA class I molecules bind and trigger cell-surface receptors specified by KIR genes. We examined whether the combination of KIR3DS1/3DL1 genes in concert with HLA-B27 genotypes is associated with susceptibility to ankylosing spondylitis (AS). Two HLA-B27-positive Caucasian populations were selected, one from Spain (71 patients and 105 controls) and another from the Azores (Portugal) (55 patients and 75 controls). All were typed for HLA-B and KIR (3DS1 and 3DL1) genes. Our results show that in addition to B27, the allele 3DS1 is associated with AS compared with B27 controls (p < 0.0001 and p < 0.003 in the Spanish population and Azoreans, respectively). We also observed that the association of KIR3DS1 to AS was found in combination with HLA-B alleles carrying Bw4-I80 in trans position in the Spanish population (30.9% in AS versus 15.2% in B27 controls, p = 0.02, odds ratio (OR) = 2.49) and in Azoreans (27.2% in AS versus 8.7% in B27 controls, p = 0.01, OR = 4.4 in Azoreans). On the other hand, 3DL1 was decreased in patients compared with B27 controls (p < 0.0001 in the Spanish population and p < 0.003 in Azoreans). The presence of this allele in combination with Bw4-I80 had a protective effect against the development of AS in the Spanish population (19.7% in AS, 35.2% in B27 controls; p = 0.03, OR = 0.45). The presence of KIR3DS1 or KIR3DL1 in combination with HLA-B*27s/HLA-B Bw4-I80 genotypes may modulate the development of AS. The susceptibility to AS could be determined by the overall balance of activating and inhibitory composite KIR-HLA genotypes.

Alleles↗

PubMed2004

[Progress on the study of HLA-Cw--review].

HLA-Cw belongs to classic HLA-I gene, HLA-Cw molecules have high polymorphism like HLA-A and B molecules. They distribute extensively on the surfaces of karyote, not only presenting endogenetic antigen to CD8+ T cells to induce specific killing effect, but also participating in immunologic reaction as the ligands of killer cell immunoglobulin-like receptor (KIR). Thus it has been valued for their relations to diseases and the functions in transplantation immunity, anti virus and anti-tumor immunity.

Autoimmune Diseases↗

PubMedDate not supplied

Cardiac allograft vasculopathy: relationship with acute cellular rejection and histocompatibility.

This article reviews the literature and summarizes the data obtained at Loyola University of Chicago about the relationship between rejection, histocompatibility, and cardiac allograft vasculopathy. Both the studies concerning the relationship between rejection and cardiac allograft vasculopathy and those evaluating the impact of histocompatibility on cardiac allograft vasculopathy have produced conflicting results. Most studies are retrospective and include a small number of patients followed up for short periods of time and treated with variable immunosuppressive regimens. In addition, the diagnosis of cardiac allograft vasculopathy is based on angiographic detection of coronary arterial abnormalities, a method that is known to underestimate the presence and severity of cardiac allograft vasculopathy. The ability to assess the impact of histocompatibility on the development of cardiac allograft vasculopathy is also limited by the lack of uniformity in the type and number of HLA variables analyzed, the extreme polymorphism of the HLA antigens and variability in serologic tissue typing techniques and quality. The results of our study suggest that complete mismatch at the HLA-B and -DR loci is associated with higher rejection rates and severity and with increased mortality. We also noted a trend toward a higher incidence of cardiac allograft vasculopathy in patients with complete mismatch at the HLA-DR locus. Future experimental and clinical studies should be done with use of molecular tissue typing techniques to further elucidate the impact of histocompatibility on cardiac allograft vasculopathy. The role of non-HLA antigens in the development of cardiac allograft vasculopathy requires further definition. Because in heart transplantation the short donor ischemic times compatible with a successful outcome limit the feasibility of prospective donor/recipient tissue typing, the development of immunosuppressive drugs that effectively reduce the detrimental effects of tissue incompatibility is crucially needed.

Adolescent↗

PubMed1977

Genetics of cell-mediated lympholysis in man.

Cell-mediated lympholysis (CML) was studied in a family containing two siblings in who genetic recombinaiton had occurred in the HLA comples. In one sibling, recombination occurred between the HLA-A locus and the HLA-B locus. In the second sibling recombination occurred between the HLA-B locus and the HLA-D locus. Strong CML activity was generated in mixed lymphocyte cultures (MLC) when stimulator and responder cells differed in HLA-A, B, and D antigens. MLC involving HLA-D differences alone did not generate CML. Weak, but definite CML activity was generated during MLC with cells differing at HLA-A and HLA-B but sharing HLA-D. HLA-B antigens were good targets for lysis in all combinations studied. HLA-A antigens were poor targets in some but not in all combinations. However, combinations where HLA-A antigens seemed to be good targets could have involved HLA-B differences due to polymorphism of HLA-B7 antigens each inherited from a different parent. HLA-D antigens did not serve as targets for lysis. In three cell experiments, excellent CML activity was generated when responder cells were stimulated by HLA-D antigens and by HLA-A and B antigens present on separate stimulator cells.

Adult↗

PubMed1999

Polymorphisms in the SOD2 and HLA-DRB1 genes are associated with nonfamilial idiopathic dilated cardiomyopathy in Japanese.

To reveal genetic risk factors of nonfamilial idiopathic cardiomyopathy (IDC) in Japanese, polymorphisms in the SOD2 and HLA-DRB1 genes were investigated in 86 patients and 380 healthy controls. There was a significant excess of homozygotes for the V allele [Val versus Ala (A allele), a polymorphism in the leader peptide of manganese superoxide dismutase at position 16] of the SOD2 gene in the patients compared with the controls (87.2% versus 74.7%, odds ratio = 2.30, p = 0.013, pc < 0.03), and a significant increase in the frequency of HLA-DRB1*1401 in the patients was confirmed (14.0% vs 4.5%, odds ratio = 3.46, p = 0.001, pc < 0.03). A two-locus analysis suggested that these two genetic markers (SOD2-VV genotype and DRB1*1401) may play a synergistic role in controlling the susceptibility to nonfamilial IDC. In addition, processing efficiency of Val-type SOD2 leader peptide in the presence of mitochondria was siginificantly lower than that of the Ala-type by 11 +/- 4%, suggesting that this lower processing efficiency was in part an underlying mechanism of the association between the SOD2-VV genotype and nonfamilial IDC.

Adolescent↗

PubMed2000

The IMGT/HLA sequence database.

The IMGT/HLA database (wwwebi.ac.uk/imgt/hla/) specialises in sequences of the polymorphic genes of the HLA system, the humanmajor histocompatibility complex (MHC). This complex is located within the 6p213 region on the short arm of human chromosome 6 and contains more than 220 genes of diverse function. Many of the genes encode proteins of the immune system and these include the 21 highly polymorphic HLA genes, which influence the outcome of clinical transplantation and confer susceptibility to a wide range of non-infectious diseases. The database contains sequences for all HLA alleles officially recognised by the WHO Nomenclature Committee for Factors of the HLA System and provides users with online tools and facilities for their retrieval and analysis. These include allele reports, alignment tools, and detailed descriptions of the source cells. The online submission tool allows both new and confirmatory sequences to be submitted directly to the WHO Nomenclature Committee. The latest version (release 1.10.0 April 2001) contains 1329 HLA alleles, 61 HLA related sequences, derived from around 3350 component sequences from the EMBL/ GenBank/DDBJ databases. The IMGT/HLA database provides a model that will be extended to provide specialist databases for polymorphic MHC genes of other species.

Alleles↗

PubMed2003

HLA-B*39 allele confers susceptibility to osteoarticular complications in human brucellosis.

OBJECTIVE: To determine the contribution of HLA gene polymorphism toward susceptibility to osteoarticular focal forms of human brucellosis. METHODS: A total of 57 patients with brucellosis, of whom 23 had osteoarticular complications, and 73 healthy volunteers were genotyped for HLA class I and class II antigens by a polymerase chain reaction-sequence specific primer technique. RESULTS: The HLA-B*39 allele was present in significantly more patients with osteoarticular complications than in the other patients (35% vs 3%; p = 0.0006, OR 15.684, 95% CI 3.453-71.231), or in the controls. CONCLUSION: The increased presence of the HLA-B39 genotype in patients with brucellosis with clinical osteoarticular manifestations suggests that this genotype confers susceptibility to developing severe osteoarticular focal forms of the disease.

Brucellosis↗

PubMed2004

HLA class II DRB high resolution genotyping by pyrosequencing: comparison of group specific PCR and pyrosequencing primers.

Sequencing of alleles of the highly polymorphic, multiple loci HLA-DRB gene family was performed by pyrosequencing using purified DNA from the 11(th) International Histocompatibility Workshop human lymphoblastiod cell lines as well as genomic DNA isolated from blood samples obtained from healthy adult volunteers. Genomic DNA was prepared from donors whose blood had been stored either frozen or as dried blood spots. Pyrosequence-based typing was optimized for identifying alleles of the HLA-DRB1, -3, -4, and -5 genes. The procedure should be applicable to other HLA loci including the class I genes HLA-A and -B that, along with HLA-DRB, are crucial for histocompatibility matching of tissue antigens during transplantation. Computer simulation of pyrosequencing data suggest that alleles of HLA-DRB1, -3, -4, and -5 were readily identifiable by pyrosequencing as were their heterozygous allelic combinations. Pyrosequencing primers were designed to specifically sequence HLA loci of interest even in a background of other amplified, closely related sequences such as alleles of the pseudogene HLA-DRB6, -7, -8, and -9. Polymorphic residues of HLA-DRB genes were identified within each pyrosequencing reaction, obtained by 50 to 70 nucleotide read lengths. Heterozygous allelic combinations of HLA genes were analyzed and compared successfully to genotyping of alleles by sequence-specific oligonucleotide probe hybridization as well as allele specific polymerase chain reaction protocols. Pyrosequence-based typing is compatible with genotyping of allelic combinations expected from heterozygous individuals, resulting in nucleotide resolution of the highly polymorphic HLA system. Using a single pyrosequence instrument, complete typing of HLA-DRB genes can be performed daily on hundreds of individuals for high resolution histocompatibility genotyping studies.

Base Sequence↗

PubMed2006

Higher prevalence of autoantibodies to insulin and GAD65 in Swedish compared to Lithuanian children with type 1 diabetes.

We compared the prevalence of beta-cell autoantibodies and genetic risk factors in Sweden and Lithuania. Ninety-six patients from Sweden and 96 from Lithuania matched for age and gender (1-15 years old, median age 9.0 years) were included. We analyzed autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA) and the protein tyrosine phosphatase like IA-2 (IA-2A) as well as risk-associated polymorphisms of HLA, insulin and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) genes. The frequency of patients positive for IAA and GADA was higher in Sweden than in Lithuania (p = 0.043 and 0.032). The differences remained even when the patients were matched for HLA, insulin and CTLA-4 risk genotypes. Patients with low levels of IAA had higher levels of HbA1c and ketones at diagnosis. The frequency of the risk haplotype DR4-DQ8 was higher in Swedish than in Lithuanian patients (p = 0.004), as well as the high-risk combination of DR4-DQ8 and DR3-DQ2 haplotypes (p = 0.009). Our results suggest that autoimmune process against insulin and GAD(65) is more common at diagnosis in children in areas with high incidence of type 1 diabetes (T1D), independent of genetic risk markers. Furthermore, the disease in patients with insulin autoantibodies seems to be clinically milder.

Adolescent↗

PubMed1988

HLA-DR and DQ DNA polymorphisms in subjects of Asian Indian and white Caucasian origin.

There is a close correspondence between serologically defined DR types and DR beta chain restriction fragment length polymorphisms (RFLPs). There is also an association between DR types and DQ alpha and DQ beta RFLPs because of linkage disequilibrium. We present the results of an analysis of DR beta, DQ alpha and DQ beta RFLPs in Asian Indians and white Caucasian subjects. DR beta RFLPs were similar in the two groups. Clearly distinguishable DR beta patterns were observed for DR1, 2, 3, 4, 5, 7 and w10. The DR beta patterns associated with DR3 were, however, also found with w6. The DR7 DR beta patterns were also found with w9. For DR specificities 1, 3, 4, 5, 7 and w10, the associated DQ alpha and DQ beta RFLPs were similar in both racial groups, but for DR2, however, marked differences were found. The DR2-positive white Caucasian subjects all possessed a single DQ alpha/DQ beta combination whereas the DQ alpha/DQ beta patterns in DR2-positive Asian Indians showed considerable heterogeneity. The pattern seen in white subjects was present in only a minority of Asians. DR-DQ relationships clearly vary in different racial groups. RFLP analysis of HLA-linked diseases in different populations should prove to be an important technique in identifying the primary genetic factor(s) in these disorders.

Genetic Linkage↗

PubMed1989

Characterization of a monoclonal antibody recognizing a polymorphic epitope mainly on HLA-DPw2 and DPw4 molecules.

A monoclonal antibody (MAb), 13.3.B4, was obtained from a murine hybridoma after fusing Sp2/0 myeloma cells with spleen cells from C3H mice immunized with mouse L cells transfected with the A1 and B1 genes of HLA-DPw4. In radiobinding-assays, MAb 13.3.B4 bound to HLA transfectants expressing DPw2 or DPw4 as well as DPw2 or DPw4 homozygous B-cell lines, while most cell lines expressing other DP determinants were negative. MAbs with known DP or other HLA class II-specificities were used to inhibit binding of MAb 13.3.B4 in a radioimmunoassay. Three MAbs demonstrated inhibition, but their pattern of reactivity with HLA homozygous B cell lines differed from that of MAb 13.3.B4. An evaluation of DNA sequence data showed that MAb 13.3.B4 reacts with all cell lines expressing DP beta-chains of type 2.1, 2.2, 4.1 or 4.2. No correlation between 13.3.B4-reactivity and expression of DP alpha-chain variants was found. The results indicate that MAb 13.3.B4 defines a polymorphic epitope which may be determined by the sequence gly-gly-pro-met at residues 84-87 of the DP beta-chain.

Animals↗

PubMed1980

Characterization, evolution, and molecular basis of a polymorphic antigenic determinant shared by HLA-A and B products.

In our search for monoclonal antibodies defining specific HLA-A,B antigens we have found a significant number of antibodies with polymorphic reactions that are not explicable with our current picture of HLA-A,B interrelationships. Analysis of one antibody (MB40.1) in some detail shows that it recognizes subsets of both A and B antigens and that it is able to split highly cross-reactive pairs of A or B antigens. These results address an outstanding difference in the serological interpretation of H-2, where these types of public reactions have been well established, from HLA, where they have been poorly characterized. Comparison of these types of serological reactions with amino acid sequence data and the apparent evolutionary stability of these broad cross-reacting determinants suggests a simple model for the molecular nature based upon limited amino acid variability and convergent evolution.

Amino Acid Sequence↗

PubMed1998

Why certain antibodies cross-react with HLA-A and HLA-G: epitope mapping of two common MHC class I reagents.

Antigen presentation at the maternal-fetal interface has been characterized by a reported lack of classical MHC class I products and the presence of a tissue-restricted, non-classical class I product with limited polymorphism, HLA-G. The lack of HLA-A, -B, and -C products at this interface would allow escape from T-cell mediated attack, while the presence of HLA-G may enable evasion of NK cell-mediated destruction. We provide evidence that in addition to HLA-G, the classical class I product HLA-C is also present in trophoblast. Specifically, cDNA from the trophoblast-derived JEG 3 cell line encodes the HLA-C-locus product, HLA-Cw*0401. This protein, obtained by in vitro transcription/translation, has biochemical characteristics identical to MHC class I products immunoprecipitated directly from the same cells. These findings are in agreement with RNA analysis and immunohistochemistry on both cell lines and primary trophoblast tissues. We report here the preferential reactivity in JEG 3 cells of two widely used monoclonal anti-MHC class I heavy chain antibodies, HC10 and HCA2, with HLA-C and HLA-G, respectively. We have mapped the epitopes recognized by these reagents to distinct areas of the alpha1 domain of the MHC class I heavy chain. HCA2 recognizes the motif xLxTLRGx spanning amino acids 77 84 present in both HLA-A and HLA-G. In contrast, HC10 may recognize a discontinuous epitope, with essential elements of the recognized motif surrounding residue 60 in the alpha1 domain of the class I heavy chain, as shown by truncation analysis. These results adequately explain the immunochemical cross-reactivity of HLA-A and HLA-G.

Amino Acid Sequence↗

PubMed1997

HLA-A, -B, -DRB1, -DQA1, and -DQB1 polymorphism in Thais.

In this study we examined HLA-A, -B, -DRB1, -DQA1, and -DQB1, gene allele, and haplotype frequencies in two ethnic Thai populations. We compared these frequencies to the known HLA class I and II allele profiles of non-Thai mainland and insular Southeast (SE) Asians. HLA-A locus gene and allele frequencies, are comparatively homogeneous in both Thai and non-Thai SE Asians. In contrast, HLA-B; -DRB1, -DQA1, and -DQB1 gene and allele frequencies, show more ethnic and geographic variation in SE Asians. Conserved haplotypes, or combinations of linked HLA class I and II alleles were detected in Thais, but at relatively low frequencies. It would appear that ethnic Thais, reflect an admixture of peoples from both the northern mainland and southern island groups of SE Asia.

China↗

PubMed1983

Primary structure of papain-solubilized human histocompatibility antigen HLA-B40 (-Bw60). An outline of alloantigenic determinants.

The primary structure of papain-solubilized human histocompatibility antigen HLA-B40 (-Bw60) has been determined. Its comparison with that of the cross-reactive HLA-B7 antigen allows for the first time a direct sequence comparison between two HLA-B locus products and an outline of the location of their alloantigenic sites. Overall sequence homology between HLA-B40 and HLA-B7 is 93%. Of 19 detected differences, 18 are located in the two amino-terminal domains (residues 1-182). Half of them are clustered in two short segments spanning residues 63-74 and 147-156, respectively, which suggests that they may encompass major sites of their alloantigenic determinants. The first of these segments is highly polymorphic in HLA and H-2 molecules. It is proposed that it may belong to a hypervariable region of class I histocompatibility antigens. The remaining substitutions are scattered through the N-terminal portions of the two external domains. Thus, in addition to the above-mentioned segments, other positions may contribute significantly to the antigenic polymorphism of these molecules.

Amino Acid Sequence↗